Pharmaceuticals are rarely distributed as pure compounds because of problems with, among others, stability, solubility, and bioavailability of the pharmaceutical itself (i.e., the active), and in most cases, are administered in a pharmaceutical formulation comprising the active, and other components, such as excipients, binders, diluents, and other delivery vehicles or systems. It is well documented that physical and chemical properties, such as stability, solubility, dissolution, permeability, and partitioning of most pharmaceuticals are directly related to the medium in which they are administered. And, in turn, the physical and chemical properties of drug-in-formulation mixtures affect the pharmacological and pharmacokinetic properties, such as absorption, bioavailability, metabolic profile, toxicity, and potency. Such effects are caused by interactions between the formulation's components and the pharmaceutical and/or interactions between the components themselves. Other properties influenced by the formulation in which a pharmaceutical is administered include mechanical properties, such as compressibility, compactability, and flow characteristics and sensory properties, such as taste, smell, and color. Thus, discovery of pharmaceutical formulations that optimize bioavailability and duration of action of the pharmaceutical and minimize undesirable properties is an important part of pharmaceutical development and research. For a general review of the subject of formulations see Howard, Introduction to Pharmaceutical Dosage Forms, Lea & Febiger, Philadelphia Pa., 4th ed., 1985; Remington: the Science and Practice of Pharmacy, Alfonso R. Gennaro ed., Mack Publishing Co. Easton, Pa., 19th ed., 1995, Chapter 83.
Formulation development is normally a tedious process, where many variables must be separately assessed. For example, if the formulation contains a pharmaceutical characterized by poor solubility, the solubility of the pharmaceutical in a range of salt concentrations; pHs; excipients; and pharmaceutical concentrations must be prepared and tested to find interactions between the pharmaceutical and excipients or interactions between excipients that affect the pharmaceutical's solubility. While some general rules exist, the effect of excipients and combinations of excipients on the physical and chemical properties of the pharmaceutical are not easily predicted. Moreover, there are over 3,000 excipients to choose from when designing pharmaceutical formulations, each having differing degrees and types of interactions with each other and with the pharmaceutical. (For a listing of generally regarded as safe (GRAS) excipients see the Code of Federal Regulations (CFR) at 21 CFR 182 and 21 CFR 184). Because of the many variables involved, industry does not have the time or resources to identify, measure, or exploit interactions between excipients and pharmaceuticals and thus cannot provide optimized pharmaceutical formulations tailored to the particular pharmaceutical. Such work would require testing hundreds to thousands of formulations a day. Assuming three hundred substances are to be tested for efficacy as excipients in a pharmaceutical formulation, even with no variations in concentrations and no physical or chemical property variations, the number of possible combinations is enormous: when two of the substances are selected, there are 45,150 possible combinations, for three components there are 4,545,100 combinations, and for four components, there are 344,291,325 possible combinations. The complexity is increased when the relative ratio of each component is considered. Unfortunately, technologies that can make many pharmaceutical-excipient combinations at the same time, then automatically feed each combination into a system for identifying the combinations that have optimized properties are not known. Today, since it is more cost effective, most pharmaceuticals are distributed and administered in the standard, un-optimized formulations, see e.g., Allen 's Compounded Formulations: U.S. Pharmacists Collection 1995 to 1998, ed. Lloyd Allen.
Paclitaxel is presently available in the United States only as a non-aqueous sub-optimal formulation concentrate for intravenous injection. An intravenous dosage regimen of 135 mg/m2 paclitaxel is recommended for previously untreated patients with carcinoma of the ovary, given every three weeks. Similar dosage regimens are recommend for other carcinomas. Paclitaxel is practically insoluble in water. The commercially-available paclitaxel formulation (Bristol-Myers Squibb) comprises 6 mg/ml of paclitaxel dissolved in Cremophor® EL (PEG-35 castor oil, polyoxyethylated castor oil) and dehydrated ethanol (50% v/v). Similar formulations are sold by other manufacturers, for example, IVAX Co. Before intravenous injection, the commercial dose must be diluted to a final concentration of 0.3 to 1.2 mg/ml prior to injection. Recommended diluents are 0.9% aqueous sodium chloride, 5% aqueous dextrose, or 0.9% sodium chloride 5% dextrose aqueous solution, or 5% dextrose in Ringer's injection (The Physician's Desk Reference, 54th edition, 881-887,Medical Economics Company (2000); Goldspiel 1994 Ann. Pharmacotherapy 28:S23-26, both of which are incorporated herein by reference).
In general, the amount of Cremophor® EL necessary to deliver the required doses of paclitaxel is significantly higher than that administered with other drugs currently formulated in Cremophor® EL. This is a particular problem since several toxic effects have been attributed to Cremophor® EL, including vasodilation, dyspnea, and hypotension. This vehicle has also been shown to cause serious hypersensitivity in laboratory animals and humans (Weiss et al., 1990, J. Clin. Oncol. 8:1263-1268). In fact, the maximum dose of paclitaxel that can be administered to mice by i.v. bolus injection is dictated by the acute lethal toxicity of the Cremophor® EL vehicle (Eiseman et al., 1994, Cancer Chemother. Pharmacol. 34:465-471).
In addition, Cremophor® EL is known to leach phthalate plasticizers such as di(2-ethylhexyl)phthalate (DEHP) from the polyvinylchloride bags and intravenous administration tubing. DEHP is known to cause hepatotoxicity in animals and is carcinogenic in rodents. Upon dilution with infusion solutions, paclitaxel Cremophor® EL formulations can result in particulate formation. In addition, fibrous precipitates of unknown composition can form in the concentrate during storage for extended periods of time. It is generally believed that the precipitates are degradation by-products of either components in the solvent or paclitaxel. In such case, filtration of the diluted Cremophor® EL/ethanol/paclitaxel formulation is necessary during administration (Goldspiel 1994 Ann. Pharmacotherapy 28:S23-26).
It has further been reported, in U.S. Pat. No. 5,504,102, that commercial grade Cremophor® EL with ethanol as a co-solvent, although effective in dissolving paclitaxel, produces injection formulations that exhibit instability over extended periods of time. In particular, pharmaceutical formulations of paclitaxel in a co-solvent of 50:50 by volume of dehydrated ethyl alcohol and commercial grade Cremophor® EL exhibit a loss of potency of greater than 60% after storage for 12 weeks at 50° C. The loss of potency is attributed to the degradation of paclitaxel during storage. Other disadvantages of. Cremophor® EL have been reported.
Some efforts have focused on limiting or eliminating Cremophor® EL by preparing paclitaxel derivatives having improved aqueous solubility over paclitaxel. Research in this area includes preparation of 2′-succinate- and amino-acid-ester prodrugs of paclitaxel (see e.g., Deutsch et al., 1989, J. Med. Chem., 32:788-792; Matthew et al., 1992, J. Med. Chem. 35:145-151). In other efforts, Greenwald et al. reported the synthesis of highly water-soluble 2′ and 7-polyethylene glycol esters of paclitaxel (Greenwald et al., 1994, Bioorganic & Medicinal Chemistry Letters 4:2465-2470), however, no data concerning the in-vivo antitumor activity of these compounds were reported (Greenwald et al., 1995, J. Org. Chem. 60:331-336). Others attempts to solve paclitaxel's aqueous-solubility problems have involved microencapsulation of paclitaxel in both liposomes and nanospheres (Bartoni et al., 1990, J. Microencapsulation 7:191-197). The liposome formulation was reported to be as effective as free paclitaxel, however, only liposome formulations containing less than 2% paclitaxel were physically stable (Sharma et al., 1994, Pharm. Res. 11:889-896). There is a need, therefore, for formulations comprising paclitaxel, derivatives, and pharmaceutically acceptable salts thereof that can deliver therapeutically effective amounts of paclitaxel and derivatives thereof that overcome the disadvantages caused by paclitaxel's insolubility and the disadvantages of Cremophor® EL.